1. Field of the Invention
The present invention relates to methods and compositions for the prevention of tolerance to medications such as pharmaceutical agents. In particular, the present invention comprises compositions and methods for the prevention of tolerance to medications used in the treatment of asthma and related pathologies.
2. Summary of the Related Art
More than fifteen million persons in the United States suffer from asthma and related inflammatory lung diseases. The number of persons with asthma is increasing both in the United States and worldwide. The morbidity associated with asthma makes it a major medical condition. Asthma is the most common chronic disease of childhood and the leading cause of school absence. Asthma in humans results in an estimated 27 million patient visits, 6 million lost workdays, and 90.5 million days of restricted activity per year. In addition to its morbidity, the mortality rate for asthma is growing worldwide. Additionally, asthmatic reactions are a growing problem for animals. In particular, the horse racing industry is affected by horses that suffer from asthmatic reactions (for a general review of asthma see Sheffer et al., The National Asthma Education Program: Expert panel report guidelines for the diagnosis and management of asthma, Med. Care 31:MS20 (1993)).
Clinically, asthma is a chronic obstructive pulmonary disease characterized by a usually reversible airway obstruction, airway inflammation and increased airway responsiveness to non-specific stimuli (see Standards for the Diagnosis and Care of Patients with Chronic Obstructive Pulmonary Disease (COPD) Am. Rev. Respir. Dis 136:225-244 (1987)). The airway obstruction during an asthma attack is due to the combination of bronchospasm (airway smooth muscles contraction), increased mucous secretion, edema of airway mucosa due to increased vascular permeability, cellular infiltration of the airway walls, and injury to airway epithelium. Hargreave et al., J. Allergy Clinical Immunol. 83:1013-1026 (1986) teaches that asthma may be triggered by a variety of causes such as allergic reactions, a secondary response to infections, industrial or occupational exposures, ingestion of certain chemicals or drugs, exercise, and vasculitis. Harrison's Principles of Internal Medicine (14.sup.th Edition Fauci et al. Eds., McGraw-Hill, New York (1998), pages 1419-1426), teaches that in many cases, there are two phases to an allergic asthma attack, an early phase and a late phase which follows 4-6 hours after bronchial stimulation. The early phase includes the immediate inflammatory response including the reactions caused by the release of cellular mediators from mast cells. The late phase reactions develop over a period of hours and are characterized histologically by an early influx of polymorphonuclear leukocytes and fibrin deposition followed later by infiltration of eosinophils. Late phase reactions and airway inflammation lead to prolonged airway hyper-reactivity and asthmatic exacerbations that may last from days to months in some subjects. Barnes et al., Am. Rev. Respir. Dis. 141:S70-S76 (1990) teaches that hyper responsiveness of the airways to nonspecific stimuli is a hallmark of this disease. Hence, at the present time, the general goals of drug therapy for asthma are prevention of bronchospasm and control of airway hyperactivity or hyper responsiveness, an indication of airway inflammation.
Conventional treatments have been predicated on the strict avoidance of all allergens, which is inherently difficult to achieve, and on therapeutic regimens based on pharmacological agents having unfortunate side effects and suboptimal pharmacokinetic properties. Hence, theophylline (a methylxanthine) for example, is characterized by substantial variability in the absorbance and clearance of theophylline. Woolock et al., Am. Respir. Crit. Care Med. 153:1481-1488 (1996) teaches that corticosteroids are used to treat late-phase and airway hyperactivity reactions. Volcheck et al., Postgrad Med. 104(3):127-136 (1998) discloses the use of cromolyn to prevent both the early and late phases of asthma inflammatory reactions. Cromolyn however, is only effective in preventing the onset of an asthma reaction if given prior to an asthma attack.
Alternative widespread treatment approaches have relied on the administration of adrenergic agonists which mimic the physiological effects of the adrenal medullary hormones and neurotransmitters of the sympathetic nervous system. .beta..sub.2 -adrenergic agonists represent important therapeutic agents in the treatment of asthma. Palmer et al., New Engl. J. Med. 331:1314-1319 (1994) teaches that salmeterol is a long-acting .beta..sub.2 adrenergic agonist that has been introduced as an adjunct to anti-inflammatory therapy in asthma management. Due to its slow onset but prolonged duration of action, the recommendation is to prescribe salmeterol for regular use, along with salbutamol for acute relief of break-through symptoms. The administration of .beta..sub.2 -adrenergic agonists, such as salmeterol, has been found to down-regulate .beta..sub.2 -adrenergic receptors. Bhagat et al. Chest 108:1235-1238 (1995) teaches that regular or prolonged use of .beta..sub.2 -adrenergic agonists is associated with poor control of asthma, increase in airway hyper responsiveness to allergen, and reduced protection against bronchoconstriction induced by exercise, histamine, methacholine and allergens challenge. Furthermore, recent reports suggest that regular use of .beta..sub.2 -agonists may also result in mild tolerance to bronchodilator response.
There are also side effects that result from treatment with adrenergic agonists because the adrenergic agonists are generally not selective for only the .beta..sub.2 -receptors, but also effect .beta..sub.1 -receptors causing cardiac stimulation. .beta..sub.2 -adrenergic agonists can be used for treatment of bronchospasm, but have no effect on airway inflammation or bronchial hyperactivity. In fact, chronic use of .beta..sub.2 -adrenergic agents alone, by down regulation of .beta..sub.2 -receptors, may worsen bronchial hyperactivity.
The development of tolerance is exemplified by treatment with the long-acting .beta..sub.2 -agonist, salmeterol. Salmeterol is a long-acting .beta..sub.2 -agonist used in the treatment of mild to moderate asthma. Several studies have shown that regular treatment with salmeterol results in loss of the bronchoprotection against different stimuli, such as exercise, methacholine, histamine. A recent study reported that tolerance to the bronchoprotective effect of salmeterol can occur as soon as after the third dose of salmeterol (see Bhagat et al., Chest 108:1235-39 (1995)). Furthermore, Lipworth, et al., Lancet 346:201-206 (1995) showed that chronic use of salmeterol results in reduction of the bronchodilator response to salbutamol.
Recent studies have sought to find approaches to counter tolerance. One approach has been that of combining bronchodilators associated with rapid reduction in bronchoprotective effect, such as salmeterolor formoterol, with corticosteroids (see Woolcock, Eur. Respir. Rev. 5:(27)142-145 (1995) and U.S. Pat. Nos. 5,049,389, 5,192,548, 5,674,860, 5,709,884, 5,736,124, 5,817,293, and 5,874,063). Despite the enthusiasm in the field, evidenced by the many reports available in the literature, such approaches have thus far failed. It has been shown that inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salrneterol (see Kalra et al. Chest 109:953-56 (1996). In contrast, high dose systemic glucocorticosteroids may prevent the tolerance to the bronchodilator effect of .beta..sub.2 -agonist.
In an attempt to counter tolerance, investigators have sought to elucidate the mechanism underlying such phenomenon. Several mechanisms have been proposed for the down-regulation of the .beta..sub.2 -adrenergic receptors. Hausdorff et al., FASEB J. 4:2881-2889 (1990) teach that tolerance stems from molecular mechanisms underlying rapid beta adrenergic receptor (hereinafter, ".beta.AR") desensitization which are in turn due to an alteration in the functioning of .beta.AR that uncouples the receptors from the stimulatory G protein Gs. This uncoupling phenomenon involves phosphorylation of .beta.AR by at least two kinases, protein kinase A (hereinafter, "PKA") and the .beta.AR kinase (hereinafter, ".beta.ARK"), which are activated under different desensitizing conditions. Receptor phosphorylation by the two kinases has also been shown to lead to desensitization of the receptor response via distinct biochemical mechanisms (see also, Liggett et al., J. Biol. Chem. 267:4740-4746 (1992); Schlericher et al., Proc. Natl. Acad. Sci. USA 90:1420-1424 (1993) and Turki et al., Am Physiol. 269(13):L709-L714 (1995)).
From a practical standpoint, the down-regulation of the .beta..sub.2 -adrenergic receptors and hence, tolerance, often results in the administration of higher dosages of the .beta..sub.2 -adrenergic agonist exposing the asthmatic patient to greater side effects. In some patients, tolerance may even reach the stage at which the patient is wholly unresponsive forcing the practitioner to adopt even less desirable approaches.
Recent reports have identified treatment regimens for antigen induced asthma based on heparin. Ahmed et al., Am. Rev. Respir. Dis. 145:566-570 (1992) for example teaches that the use of glycosaminoglycan heparin prevents bronchoconstrictor responses induced by stimuli that produce immunologic mast-cell degranulation in sheep, without attenuating agonist-induced bronchoconstriction. Similarly, Lucio et al., Amer. Physiol. Soc. 73(3):1093-1101 (1992) teaches that immunologic mast cell-mediated responses and histamine release are attenuated by heparin. Other work in the field has also demonstrated the prevention of exercise induced asthma with inhaled heparin (see for example, Ahmed et al., N. Eng. J. Med. 329:90-95 (1993) and Ahmed, Respiratory Drug Delivery IV, 55-63).
Heparin has been used for a variety of purposes. Lane et al. Chemical and Biological Properties, Clinical Applications, Edward Arnold Ed. London (1989) teaches that heparin is a highly sulfated, unbranched glycosaminoglycan used in the clinical practice as an anticoagulant agent. This activity results from heparin's ability to bind some of the residues of antithrombin III (AT-III), accelerating the neutralization by AT-III of activated clotting factors and preventing the conversion of prothrombin to thrombin. Larger amounts of heparin can inactivate thrombin and earlier clotting factors, preventing conversion of fibrinogen to fibrin. Heparin is synthesized in mast cells as a proteoglycan and is particularly abundant in the lungs of various animals. Heparin is not a specific compound of fixed molecular weight, but is actually a heterogeneous mixture of variably sulfated polysaccharide chains composed of repeating units of D-glucosamine and L-iduronic acid. Despite the extensive heparin literature for selected asthma applications, to date the use of heparin to address bronchodilator induced tolerance has not been investigated.
Thus, there is a long felt need for methods and compositions for the treatment of asthma and related pathologies. Such methods should address the shortcomings of traditional therapeutic approaches. More specifically, there is a need for novel modalities and compositions capable of preventing the tolerance that is developed by use of traditional bronchodilators. Such novel approaches should prevent the down-regulation of .beta..sub.2 -adrenergic receptors in response to the use of .beta..sub.2 -adrenergic agonists. Moreover, there is a need for methods and compositions capable of preventing tolerance developed in response to use of .beta..sub.2 -adrenergic agonists for the treatment of asthma which are easily administered, and which minimize side effects as compared to current protocols. Ideally such compositions should be easily administered (e.g. self-administrated inhalation).